| First Author | Kemp BA | Year | 2014 |
| Journal | Circ Res | Volume | 115 |
| Issue | 3 | Pages | 388-99 |
| PubMed ID | 24903104 | Mgi Jnum | J:250453 |
| Mgi Id | MGI:5920196 | Doi | 10.1161/CIRCRESAHA.115.304110 |
| Citation | Kemp BA, et al. (2014) AT(2) receptor activation induces natriuresis and lowers blood pressure. Circ Res 115(3):388-99 |
| abstractText | RATIONALE: Compound 21 (C-21) is a highly selective nonpeptide AT2 receptor (AT2R) agonist. OBJECTIVE: To test the hypothesis that renal proximal tubule AT2Rs induce natriuresis and lower blood pressure in Sprague-Dawley rats and mice. METHODS AND RESULTS: In rats, AT2R activation with intravenous C-21 increased urinary sodium excretion by 10-fold (P<0.0001); this natriuresis was abolished by direct renal interstitial infusion of specific AT2R antagonist PD-123319. C-21 increased fractional excretion of Na(+) (P<0.05) and lithium (P<0.01) without altering renal hemodynamic function. AT2R activation increased renal proximal tubule cell apical membrane AT2R protein (P<0.001) without changing total AT2R expression and internalized/inactivated Na(+)-H(+) exchanger-3 and Na(+)/K(+)ATPase. C-21-induced natriuresis was accompanied by an increase in renal interstitial cGMP (P<0.01); C-21-induced increases in urinary sodium excretion and renal interstitial cGMP were abolished by renal interstitial nitric oxide synthase inhibitor l-N(6)-nitroarginine methyl ester or bradykinin B2 receptor antagonist icatibant. Renal AT2R activation with C-21 prevented Na(+) retention and lowered blood pressure in the angiotensin II infusion model of experimental hypertension. CONCLUSIONS: AT2R activation initiates its translocation to the renal proximal tubule cell apical membrane and the internalization of Na(+)-H(+) exchanger-3 and Na(+)/K(+)ATPase, inducing natriuresis in a bradykinin-nitric oxide-cGMP-dependent manner. Intrarenal AT2R activation prevents Na(+) retention and lowers blood pressure in angiotensin II-dependent hypertension. AT2R activation holds promise as a renal proximal tubule natriuretic/diuretic target for the treatment of fluid-retaining states and hypertension. |
